This application proposes an integrated set of research aims and training experiences with the goal of fostering the applicant's development into an independent researcher conducting translational studies of disease modifying mechanisms in neurodegeneration. Alzheimer disease with psychosis (AD+P) occurs in approximately half of all Alzheimer disease subjects and identifies a phenotype with accelerated cognitive and functional decline in comparison to AD subjects without psychosis (AD-P). Underlying the rapid cognitive decline of AD+P is increased neocortical synaptic pathology. A growing pool of evidence implicates soluble amyloid beta (A) oligomers as a primary toxic agent in AD, which initiates NMDA receptor dependent mechanisms of LTD (LTDNMDAR), resulting in synapse loss. Our lab has been conducting investigations of how this process may be modified in AD+P. Recent genome wide association study of AD+P identified an association of the VSNL1 gene with AD+P. VSNL1 encodes VILIP-1, a neuronal calcium sensor (NCS) in a subfamily of closely related proteins which are necessary for LTDNMDAR. VILIP-1 has also recently been identified as a peripheral biomarker of AD. Preliminary data indicates that VILIP-1 is reduced in the cortex in a mouse model of A overproduction, and in post-mortem dorsolateral prefrontal cortex tissue from AD-P subjects compared to control subjects. The decrease in VILIP-1 was greater in AD-P than in AD+P subjects (control>AD+P>AD-P). These findings have led me to hypothesize that VILIP-1 protein expression is decreased in response to A, reducing vulnerability to soluble A-induced synapse loss by counteracting A initiated LTDNMDAR, and this neuroprotective effect is attenuated in AD+P. I will test this hypothesis in a set of highly translational aims combining human post-mortem, rodent model, and primary neuronal culture studies. The planned studies will provide me training in human tissue studies of AD, advanced quantitative fluorescence microscopy, experimental manipulation of primary neuronal cultures, and RNAi. Successful completion of the proposed Aims will indicate the direction of VILIP-1 expression alteration in the presence of A; will reveal whether altered expression of VILIP-1 modifies the impact of A on dendritic spines, and; will lead to further studies investigating of the effects of VILIP-1 on mechanisms of LTD. Ultimately, understanding the mechanisms of VILIP-1 in AD+P will direct future therapeutic strategies to improve the health and well- being of older Americans suffering from Alzheimer disease. PUBLIC HEALTH RELEVANCE: Psychosis in Alzheimer's disease (AD+P) is a highly heritable phenotype of AD that occurs in 40-60% of the estimated 5.2 million individuals with AD in the United States of America. AD+P presents with an accelerated trajectory of cognitive and functional decline, which is associated with greater neocortical synaptic pathology. Current treatments for AD+P have limited efficacy and are associated with substantial toxicity, resulting in increased risk of death. Understanding distinct causal neurobiological factors, like the role of VILIP-1 in AD+P, will lead to improved therapeutic strategies and profoundly impact patients, caregivers, and society as a whole.